Phenotypes Associated with This Genotype

Genotype
MGI:7339154

• Allelic Composition: Lamp2^tm1.2Ces/Y
• Genetic Background: involves: 129 * 129S4/SvJae * 129S6/SvEvTac * C57BL/6 * SJL

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

mortality/aging

neonatal lethality, incomplete penetrance ( J:328713 )

♂ • neonatal death in about 25% of hemizygous males

♂ • surviving males exhibit normal survival

growth/size/body

increased heart weight ( J:328713 )

♂ • heart to body weight is increased at 40 weeks of age

cardiac hypertrophy ( J:328713 )

♂ • males develop significant cardiac hypertrophy after 20 weeks of age

♂ • mice treated for 2 weeks with cyclosporine A that blocks mitochondrial autophagy show a attenuation of cardiac hypertrophy, however fractional shortening and fibrosis are unaffected

heart left ventricle hypertrophy ( J:328713 )

♂ • left ventricular hypertrophy by 20 weeks of age; echocardiograms show hypertrophy of the intra-ventricular septum and posterior wall

decreased birth body size ( J:328713 )

♂ • surviving males are initially smaller but achieve comparable size and weight by 12 weeks of age

cardiovascular system

increased cardiac muscle glycogen level ( J:328713 )

♂ • hearts contain approximately 2 times the glycogen content as wild-type hearts

♂ • however, no PAS+ inclusions are seen

abnormal myocardial fiber morphology ( J:328713 )

• left ventricle myocytes have abundant bilayer membrane vesicles containing inclusions composed of cytoplasmic remnants, partially degraded organelles, and amorphous materials characteristic of autophagosomes that disrupt the normal sarcomere organization

• lysosomes are dispersed throughout the cytosol instead of being clustered in the perinuclear regions

increased heart weight ( J:328713 )

♂ • heart to body weight is increased at 40 weeks of age

cardiac hypertrophy ( J:328713 )

♂ • males develop significant cardiac hypertrophy after 20 weeks of age

♂ • mice treated for 2 weeks with cyclosporine A that blocks mitochondrial autophagy show a attenuation of cardiac hypertrophy, however fractional shortening and fibrosis are unaffected

heart left ventricle hypertrophy ( J:328713 )

♂ • left ventricular hypertrophy by 20 weeks of age; echocardiograms show hypertrophy of the intra-ventricular septum and posterior wall

dilated heart left ventricle ( J:328713 )

♂

cardiac fibrosis ( J:328713 )

• mice show progressive myocardial fibrosis, with interstitial fibrosis at 20 weeks and both interstitial fibrosis and areas of scarring by 40 weeks of age

decreased cardiac muscle contractility ( J:328713 )

• aged (about 40 weeks) mice show decreased fractional shortening

irregular heartbeat ( J:328713 )

♂ • pacing induces ventricular arrhythmias in 75% of mice

♂ • however, no difference in average sinus heart rate is seen and mice do not exhibit ventricular pre-excitation or spontaneous arrhythmias

atrioventricular block ( J:328713 )

• intermittent atrio-ventricular block in 60% of mice

prolonged PR interval ( J:328713 )

♂

abnormal sinoatrial node conduction ( J:328713 )

• 15-week-old mice show transient sinus node arrest

abnormal myocardial fiber physiology ( J:328713 )

• durations of contraction and relaxation are prolonged in myocytes

• however, the extent of shortening or relaxation is not different in cardiomyocytes

• the mean amplitude of calcium transients is higher in myocytes

• catecholamines further increase mean calcium transient amplitudes to higher levels than in controls indicating increased sensitivity to catecholamines

• marker analysis indicates incomplete lysosome biogenesis

• catecholamines produce spontaneous and frequent sarcoplasmic reticulum calcium release events in about 75% of myocytes compared to 8% of wild-type myocytes

cardiomyopathy ( J:328713 )

♂ • mice develop progressive cardiomyopathy

muscle

increased cardiac muscle glycogen level ( J:328713 )

♂ • hearts contain approximately 2 times the glycogen content as wild-type hearts

♂ • however, no PAS+ inclusions are seen

abnormal myocardial fiber morphology ( J:328713 )

• left ventricle myocytes have abundant bilayer membrane vesicles containing inclusions composed of cytoplasmic remnants, partially degraded organelles, and amorphous materials characteristic of autophagosomes that disrupt the normal sarcomere organization

• lysosomes are dispersed throughout the cytosol instead of being clustered in the perinuclear regions

heart left ventricle hypertrophy ( J:328713 )

♂ • left ventricular hypertrophy by 20 weeks of age; echocardiograms show hypertrophy of the intra-ventricular septum and posterior wall

decreased cardiac muscle contractility ( J:328713 )

• aged (about 40 weeks) mice show decreased fractional shortening

cardiomyopathy ( J:328713 )

♂ • mice develop progressive cardiomyopathy

homeostasis/metabolism

increased cardiac muscle glycogen level ( J:328713 )

♂ • hearts contain approximately 2 times the glycogen content as wild-type hearts

♂ • however, no PAS+ inclusions are seen

abnormal autophagy ( J:328713 )

• autophagy is stimulated in myocytes but the later stages in the processing of autophagosomes are blocked, resulting in accumulated autophagosomes, absent phagolysosomes, and myocytes that are unable to clear cellular debris indicating a block in autophagy at the step of formation of autolysosomes

increased circulating troponin T level ( J:328713 )

♂ • elevation of serum cardiac troponin T, indicating an ongoing myocardial injury

cellular

abnormal autophagy ( J:328713 )

• autophagy is stimulated in myocytes but the later stages in the processing of autophagosomes are blocked, resulting in accumulated autophagosomes, absent phagolysosomes, and myocytes that are unable to clear cellular debris indicating a block in autophagy at the step of formation of autolysosomes

behavior/neurological

behavior/neurological phenotype ( J:328713 )

♂N • surviving males exhibit normal voluntary activity

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Danon disease		DOID:0050437	OMIM:300257	J:328713